Hepatitis C virus (HCV) is one of the major factors causing chronic hepatitis and liver cirrhosis, and is an important factor from the etiological point of view in terms of hepatocellular carcinoma. Despite the development of a triple therapy using the combination of interferon-α (IFN-α), ribavirin (RBV), and telaprevir or boceprevir as direct acting antivirals (DAA), sustained virological response rates, toxicity, and resistance still remain as major problems to be solved. Accordingly, there is a need for the development of a novel antivirus that can intervene in several steps of the viral life cycle while exhibiting lower side effects.
HCV relies on host machineries through its life cycle. Among various cellular factors, cyclophilin A (CypA) has the activity of peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the isomerization of a prolyl peptide bond, and is thought to be involved in protein folding of nonstructural viral proteins (e.g., NS2, NS5A, and NS5B). Accordingly, CypA is thought to be as an attractive target for potential anti-HCV materials.
Recently, CypA inhibitors were suggested as a therapeutic option for the treatment of hepatitis C virus. The three different kinds of non-immunosuppressive analogs of cyclosporine (CsA), i.e. Alisporivir; Dehio-025, SCY-635, and NIM811, exhibited effects on the HCV replication. The combined use of a virus-specific inhibitor and a CypA inhibitor was shown to minimize toxicities by reducing the administration frequency of individual drugs. The major advantage of the CypA inhibitor is the high genetic barrier to the sustained antiviral responses and resistance, compared to that of DAA. Although CsA analogs have useful effects against the HCV infection, the clinical safety profiles of these analogs are still under analysis. Recently, the Alisporivir test was stopped due to the occurrence of life-threatening pancreatitis observed in a few patients. Accordingly, the safety issue associated with CsA-based inhibitors requires the development of a novel and improved CypA inhibitor, as a strong anti-HCV material.